Gyrase inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds of the formula I:  
                 
 
     or a pharmaceutically acceptable derivative or prodrug thereof. The compounds are useful as inhibitors of bacterial gyrase activity. The present invention also relates to methods for treating bacterial infections in mammala. The present invention also relates to methods for decreasing bacterial quantity in a biological sample.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication No. 60/256,094 filed Dec. 15, 2000 and U.S. ProvisionalPatent Application No. 60/275,292 filed Mar. 13, 2001, the contents ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of medicinal chemistry and relatesto compounds, and pharmaceutical compositions thereof, that inhibitbacterial gyrases. The compounds are useful as inhibitors of bacterialgyrase activity. The present invention also relates to methods fortreating bacterial infections in mammals. The present invention alsorelates to methods for decreasing bacterial quantity in a biologicalsample.

BACKGROUND OF THE INVENTION

[0003] Bacterial resistance to antibiotics has long been recognized, andit is today considered to be a serious worldwide health problem. As aresult of resistance, some bacterial infections are either difficult totreat with antibiotics or even untreatable. This problem has becomeespecially serious with the recent development of multiple drugresistance in certain strains of bacteria, such as Streptococcuspneumoniae (SP), Mycobacterium tuberculosis, and Enterococcus. Theappearance of vancomycin resistant enterococcus was particularlyalarming because vancomycin was formerly the only effective antibioticfor treating this infection, and had been considered for many infectionsto be the drug of “last resort”. While many other drug-resistantbacteria do not cause life-threatening disease, such as enterococci,there is the-fear that the genes which induce resistance might spread tomore deadly organisms such as Staphylococcus aureus, where methicillinresistance is already prevalent (De Clerq, et al., Current Opinion inAnti-infective Investigational Drugs, 1999, 1, 1; Levy, “The Challengeof Antibiotic Resistance”, Scientific American, March, 1998).

[0004] Another concern is how quickly antibiotic resistance can spread.For example, until the 1960's SP was universally sensitive topenicillin, and in 1987 only 0.02% of the SP strains in the U.S. wereresistant. However, by 1995 it was reported that SP resistance topenicillin was about seven percent and as high as 30% in some parts ofthe U.S. (Lewis, FDA Consumer magazine (September, 1995); Gershman inThe Medical Reporter, 1997).

[0005] Hospitals, in particular, serve as centers for the formation andtransmission of drug-resistant organisms. Infections occurring inhospitals, known as nosocomial infections, are becoming an increasinglyserious problem. of the two million Americans infected in hospitals eachyear, more than half of these infections resist at least one antibiotic.The Center for Disease Control reported that in 1992, over 13,000hospital patients died of bacterial infections that were resistant toantibiotic treatment (Lewis, “The Rise of Antibiotic-ResistantInfections”, FDA Consumer magazine, September, 1995).

[0006] As a result of the need to combat drug-resistant bacteria and theincreasing failure of the available drugs, there has been a resurgentinterest in discovering new antibiotics. One attractive strategy fordeveloping new antibiotics is to inhibit DNA gyrase, a bacterial enzymenecessary for DNA replication, and therefore; necessary for bacterialcell growth and division. Gyrase activity is also associated with eventsin DNA transcription, repair and recombination.

[0007] Gyrase is one of the topoisomerases, a group of enzymes whichcatalyze the interconversion of topological isomers of DNA (seegenerally, Kornberg and Baker, DNA Replication, 2d Ed., Chapter 12,1992, W. H. Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6,425; Drlica and Zhao, Microbiology and Molecular Biology Reviews, 1997,61, 377). Gyrase itself controls DNA supercoiling and relievestopological stress that occurs when the DNA strands of a parental duplexare untwisted during the replication process. Gyrase also catalyzes theconversion of relaxed, closed circular duplex DNA to a negativelysuperhelical form which is more favorable for recombination. Themechanism of the supercoiling reaction involves the wrapping of gyrasearound a region of the DNA, double strand breaking in that region,passing a second region of the DNA through the break, and rejoining thebroken strands. Such a cleavage mechanism is characteristic of a type IItopoisomerase. The supercoiling reaction is driven by the binding of ATPto gyrase. The ATP is then hydrolyzed during the reaction. This ATPbinding and subsequent hydrolysis cause conformational changes in theDNA-bound gyrase that are necessary for its activity. It has also beenfound that the level of DNA supercoiling (or relaxation) is dependent onthe ATP/ADP ratio. In the absence of ATP, gyrase is only capable ofrelaxing supercoiled DNA.

[0008] Bacterial DNA gyrase is a 400 kilodalton protein tetramerconsisting of two A (GyrA) and two B subunits (GyrB). Binding. andcleavage of the. DNA is associated with GyrA, whereas ATP is bound andhydrolyzed by the GyrB protein. GyrB consists of an amino-terminaldomain which has the ATPase activity, and a carboxy-terminal domainwhich interacts with GyrA and DNA. By contrast, eukaryotic type IItopoisomerases are homodimers that can relax negative and positivesupercoils, but cannot introduce negative supercoils. Ideally, anantibiotic based on the inhibition of bacterial DNA gyrase would beselective for this enzyme and be relatively inactive against theeukaryotic type II topoisomerases.

[0009] The widely-used quinolone antibiotics inhibit bacterial DNAgyrase. Examples of the quinolones include the early compounds such asnalidixic acid and oxolinic acid, as well as the later, more potentfluoroquinolones such as norfloxacin, ciprofloxacin, and trovafloxacin.These compounds bind to GyrA and stabilize the cleaved complex, thusinhibiting overall gyrase function, leading to cell death. However, drugresistance has also been recognized as a problem for this class ofcompounds (WHO Report, “Use of Quinolones in Food Animals and PotentialImpact on Human Health”, 1998). With the quinolones, as with otherclasses of antibiotics, bacteria exposed to earlier compounds oftenquickly develop cross-resistance to more potent compounds in the sameclass.

[0010] There are fewer known inhibitors that bind to GyrB. Examplesinclude the coumarins, novobiocin and coumermycin A1, cyclothialidine,cinodine, and clerocidin. The coumarins have been shown to bind to GyrBvery tightly. For example, novobiocin makes a network of hydrogen bondswith the protein and several hydrophobic contacts. While novobiocin andATP do appear to bind within the ATP binding site, there is minimaloverlap in the bound orientation of the two compounds. The overlappingportions are the sugar unit of novobiocin and the ATP adenine (Maxwell,Trends in Microbiology, 1997, 5, 102).

[0011] For coumarin-resistant bacteria, the most prevalent pointmutation is at a surface arginine residue that binds to the carbonyl ofthe coumarin ring (Arg136 in E. coli GyrB). While enzymes with thismutation show lower supercoiling and ATPase activity, they are also lesssensitive to inhibition by coumarin drugs (Maxwell, Mol. Microbiol.,1993, 9, 681).

[0012] Despite being potent inhibitors of gyrase supercoiling, thecoumarins have not been widely used as antibiotics. They are generallynot suitable due to their low permeability in bacteria, eukaryotictoxicity, and poor water solubility (Maxwell, Trends in Microbiology,1997, 5, 102). It would be desirable to have a new, effective GyrBinhibitor that overcomes these drawbacks and, preferably, does not relyon binding to Arg136 for activity. Such an inhibitor would be anattractive antibiotic candidate, without a history of resistanceproblems that plague other classes of antibiotics.

[0013] As bacterial resistance to antibiotics has become an importantpublic health problem, there is a continuing need to develop newer andmore potent antibiotics. More particularly, there is a need forantibiotics that represent a new class of compounds not previously usedto treat bacterial infection. Such compounds would be particularlyuseful in treating nosocomial infections in hospitals where theformation and transmission of resistant bacteria are becomingincreasingly prevalent.

DESCRIPTION OF THE INVENTION

[0014] It has now been found that.compounds of this invention andpharmaceutical compositions thereof are useful in treating bacterialinfections. One embodiment of this invention relates to a method oftreating a bacterial infection in a mammal in need thereof, comprisingthe step of administering to said mammal a therapeutically effectiveamount of a compound of formula I:

[0015] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0016] Z is O or N—R⁴;

[0017] W is nitrogen or CR^(a);

[0018] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or—N(R⁷)₂;

[0019] R¹ is an aryl or heteroaryl ring, wherein said ring is optionallysubstituted by up to four R⁹; wherein an R⁹ substituent in theortho-position of R¹ taken together with R² may form a fused,unsaturated or partially unsaturated, optionally substituted 5-8membered ring having 0-2 ring heteroatoms selected from nitrogen,oxygen, or sulfur;

[0020] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0021] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0022] y is 1-6;

[0023] R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R,(CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂,CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂;

[0024] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0025] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0026] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a,four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0027] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0028] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂;

[0029] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0030] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—;

[0031] each m and n are independently selected from zero or one;

[0032] and R¹⁰ is selected from R⁷ or Ar.

[0033] As used herein, the following definitions shall apply unlessotherwise indicated. In addition, unless otherwise indicated, functionalgroup radicals are independently selected.

[0034] The term “aliphatic” as used herein means straight-chain,branched or cyclic C₁-C₁₂ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation but which are notaromatic. For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl”, and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are. completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

[0035] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” meansalkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. The term “halogen” means F, Cl, Br, or I.

[0036] The term “heteroatom” means N, O, or S and includes any oxidizedform of nitrogen and sulfur, and the quaternized form of any basicnitrogen.

[0037] The term “carbocycle”, “carbocyclyl”, or “carbocyclic” as usedherein means an aliphatic ring system having three to fourteen members.The term “carbocycle”, “carbocyclyl”, or “carbocyclic” whether saturatedor partially unsaturated, also refers to rings that are optionallysubstituted. The terms “carbocyclyl” or “carbocyclic” also includealiphatic rings that are fused to one or more aromatic or nonaromaticrings, such as in a decahydronaphthyl or tetrahydronaphthyl, where theradical or point of attachment is on the aliphatic ring.

[0038] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in aindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

[0039] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein includes non-aromatic ring systems having five to fourteenmembers, preferably five to ten, in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

[0040] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromaticring groups having five to fourteen members. Examples of heteroarylrings include 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinoline, tetrahydroisoquinoline, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term,“heteroaryl ring” or the term“heteroaromatic”.

[0041] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph),—CH₂(Ph), substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O) R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C((═NH)—N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),—(CH₂)_(y)NHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is H, a substituted orunsubstituted aliphatic group, an unsubstituted heteroaryl orheterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph), substituted—O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and V is a linkergroup. Examples of substituents on the aliphatic group or the phenylring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen,alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

[0042] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Examples of suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring include those listed above for the unsaturated carbonof an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*,═NN(R*)₂, ═N—, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,where each R* is independently selected from hydrogen, an unsubstitutedaliphatic group or a substituted aliphatic group. Examples ofsubstituents on the aliphatic group include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0043] Suitable substituents on the nitrogen of an aromatic ornon-aromatic heterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, and —NR⁺SO₂R⁺; wherein R⁺ is H, an aliphatic group, asubstituted aliphatic group, phenyl (Ph), substituted Ph, —O(Ph),substituted —O(Ph), CH₂(Ph), substituted CH₂(Ph), or an unsubstitutedheteroaryl or heterocyclic ring. Examples of substituents on thealiphatic group or the phenyl ring include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0044] The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200.Examples of linkers include a saturated or unsaturated C₁₋₆ alkylidenechain which is optionally substituted, and wherein one or two saturatedcarbons of the chain are optionally replaced by —C(O)—, —C(O)C(O)—,—CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—, —OC(O)NH—,—NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

[0045] The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

[0046] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

[0047] It will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention.

[0048] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

[0049] One preferred embodiment of this invention relates to a method oftreating a bacterial infection in a mammal in need thereof, comprisingthe step of administering to said mammal a therapeutically effectiveamount of a compound having the formula Ia or Ib:

[0050] or a pharmaceutically acceptable derivative or prodrug thereof,wherein R¹, R², R³, R⁴, and R⁵ are as described above.

[0051] Examples of preferred R¹ include optionally substituted phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl,imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl,aminobenzimidazole, and indolyl. Preferred R⁹, if present, on the R¹aryl or heteroaryl ring include halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂,CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)RCO₂R⁶,N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, orSO₂N(R⁶)₂. Examples of such R⁹ groups include, but are not limited to,pyrrol-2,5-dione, NR₂, OR, CO₂H, NO₂, OH, NHCOR, NHCO₂R, NHCH₂CO₂R,NH(CH₂)₂NHCO₂R, CH₂CO₂R, CF₃, SO₂R, NHCH(CH₂OH)CO₂H,N—SO₂Me-piperidinyl, SMe, NH(CH₂)₂NH₂, and piperidinyl.

[0052] Preferred R² and R³ groups include halogen, CN, CO₂R⁶, OR⁶, andR⁶. Examples of preferred R³ groups include Br, F, Cl, COOH, CN, OMe,methyl, ethyl, t-butyl, CF₃, OH, and OBn.

[0053] Examples of preferred R⁵ include CO₂(aliphatic), C(═NH)—NH₂, andCON(R⁷)₂ such as CO(piperidin-1-yl), CONHEt, CONHMe, CONH(cyclopropyl),CONH(isopropyl), CONH(propyl), CONH(pyrrolidinyl), CO₂Et, and CO₂Me.

[0054] Preferred compounds of formula Ia and Ib include those having oneor more, or most preferably all, of the features selected from the groupconsisting of:

[0055] (a) R¹ is an optionally substituted aryl or heteroaryl ring;

[0056] (b) R² and R³ are each independently selected from halogen, CN,CO₂R⁶, OR⁶, or R⁶;

[0057] (c) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or(CH₂)_(y)N(R⁷)₂; and

[0058] (d) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂,NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.

[0059] More preferred compounds of formula Ia and Ib include thosehaving one or more, or most preferably all, of the features selectedfrom the group-consisting of:

[0060] (a) R¹ is an optionally substituted ring selected from phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl,imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl,aminobenzimidazole, or indolyl;

[0061] (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen;

[0062] (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen;

[0063] (d) R⁴ is hydrogen or (CH₂)_(y)R²;

[0064] (e) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and

[0065] (f) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.

[0066] Selected compounds of formula Ia are set forth in Table 1 below.TABLE 1 No. Ia- Structure 1

2

3

4

5

6

7

8

9

10

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[0067] Selected compounds of formula Ib are shown in Table 2 below.TABLE 2 No. Ib- Structure 1

2

3

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5

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[0068] Another embodiment of this invention relates to compounds offormula IIa or IIb

[0069] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0070] W is nitrogen or CR^(a);

[0071] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or—N(R⁷)₂;

[0072] R¹ is an aryl or heteroaryl ring, wherein said ring is optionallysubstituted by up to four R⁹; wherein an R⁹ substituent in theortho-position of R¹ taken together with R² may form a fused,unsaturated or partially unsaturated, optionally substituted 5-8membered ring having 0-2 ring heteroatoms selected from nitrogen,oxygen, or sulfur;

[0073] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0074] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0075] y is 1-6;

[0076] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0077] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0078] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0079] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0080] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂;

[0081] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0082] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; and

[0083] each m and n are independently selected from zero or one.

[0084] Examples of preferred R¹ include optionally substituted phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl,imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl,aminobenzimidazole, and indolyl. Preferred R⁹, if present, on the R¹aryl or heteroaryl ring of formula IIa or IIb include halogen, CN, oxo,R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, and N(R)T_(n)CO₂R⁶.Examples of such R⁹ groups include, but are not limited to,pyrrol-2,5-dione, NR₂, OR, CO₂H, NO₂, OH, NHCOR, NHCO₂R, NHCH₂CO₂R,NH(CH₂)₂NHCO₂R, CH₂CO₂R, CF₃, SO₂R, NHCH(CH₂OH)CO₂H,N—SO₂Me-piperidinyl, SMe, NH(CH₂)₂NH₂, and piperidinyl.

[0085] Preferred R² and R³ groups include halogen, CN, CO₂R⁶, OR⁶, andR⁶. Examples of preferred R³ groups include Br, F, Cl, COOH, CN, OMe,methyl, ethyl, t-butyl, CF₃, OH, and OBn.

[0086] Preferred compounds of formulae IIa and IIb include those havingone or more, or most preferably all, of the features selected from thegroup consisting of:

[0087] (a) R¹ is an optionally substituted aryl or heteroaryl ring;

[0088] (b) R² and R³ are each independently selected from halogen, CN,CO₂R⁶, OR⁶, or R⁶;

[0089] (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂,NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.

[0090] More preferred compounds of formula IIa and IIb include thosehaving one or more, or most preferably all, of the features selectedfrom the group consisting of:

[0091] (a) R¹ is an optionally substituted ring selected from phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl,imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl,aminobenzimidazole, or indolyl;

[0092] (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen;

[0093] (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen;

[0094] (d) R⁴ is hydrogen or (CH₂)_(y)R²; and

[0095] (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.

[0096] Another embodiment of this invention relates to compounds offormula IIIa or IIIb:

[0097] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0098] W is nitrogen or CR^(a);

[0099] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or—N(R⁷)₂;

[0100] Ring A is optionally substituted with up to three R⁹; whereinwhen an R⁹ substituent is in the ortho-position of Ring A, said R⁹substituent may be taken together with R² to form an optionallysubstituted 5-7 membered ring containing 0-2 ring heteroatoms selectedfrom nitrogen, oxygen, or sulfur;

[0101] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0102] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0103] y is 1-6;

[0104] R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R,(CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂,CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂;

[0105] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0106] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0107] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0108] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0109] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂;

[0110] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0111] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—;

[0112] each m and n are independently selected from zero or one;

[0113] and R¹⁰ is selected from R⁷ or Ar.

[0114] Preferred R⁹, if present, on Ring A of formulae IIIa and IIIbinclude halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶,CON(R)COR⁶, and N(R)T_(n)CO₂R⁶. Examples of such R⁹ groups include, butare not limited to, pyrrol-2,5-dione, NR₂, OR, CO₂H, NO₂, OH, NHCOR,NHCO₂R, NHCH₂CO₂R, NH(CH₂)₂NHCO₂R, CH₂CO₂R, CF₃, SO₂R, NHCH(CH₂OH)CO₂H,N—SO₂Me-piperidinyl, SMe, NH(CH₂)₂NH₂, and piperidinyl.

[0115] Preferred R² and R³ groups include halogen, CN, CO₂R⁶, OR⁶, andR⁶. Examples of preferred R³ groups include Br, F, Cl, COOH, CN, OMe,methyl, ethyl, t-butyl, CF₃, OH, and OBn.

[0116] Examples of preferred R⁵ include CO₂(aliphatic), C(═NH)—NH₂, andCON(R⁷)₂ such as CO(piperidin-1-yl), CONHEt, CONHMe, CONH(cyclopropyl),CONH(isopropyl), CONH(propyl), CONH(pyrrolidinyl), CO₂Et, and CO₂Me.

[0117] Preferred compounds of formulae IIIa and IIIb include thosehaving one or more, or most preferably all, of the features selectedfrom the group consisting of:

[0118] (a) R² and R³ are each independently selected from halogen, CN,CO₂R⁶, OR⁶, or R⁶;

[0119] (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or(CH₂)_(y)N(R⁷)₂; and

[0120] (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂,NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.

[0121] More preferred compounds of formula IIIa and IIIb include thosehaving one or more, or most preferably all, of the features selectedfrom the group consisting of:

[0122] (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen;

[0123] (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen;

[0124] (c) R⁴ is hydrogen or (CH₂)_(y)R²;

[0125] (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and

[0126] (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂,CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.

[0127] The compounds of this invention may be prepared in general bymethods known to those skilled in the art for analogous compounds, asillustrated by the general Schemes I through VII shown below. Thedetails of the conditions used for preparing these compounds are setforth in the Examples.

[0128] The compounds 2 are prepared by treating a solution of4-bromo-2-nitroaniline (1) in DMF with an arylboronic acid (1.2equivalents), potassium phosphate (1.3 equivalents), anddichloro-(diphenylphosphinoferrocene)palladium (0.1 equivalent). Theresulting mixture is heated at 95° C. for 18 hours then cooled to roomtemperature and diluted with ethyl acetate. The crude product isisolated by aqueous work-up then concentrated in vacuo. The concentrateis purified by silica gel chromatography to afford 2. A wide variety ofsubstitutions on the aryl ring are amenable to this reaction. Examplesof suitable substituted and unsubstituted aryl groups include, but arenot limited to, those set forth in Table 1 above.

[0129] Compound 3 is prepared by treating a solution of 2 in ethylacetate with 10% palladium on carbon (0.1 g/mmol) and the resultingsuspension hydrogenated at 40 psi while shaking at ambient temperaturefor 2 hours. The catalyst is removed by filtration and the filtrateconcentrated in vacuo to afford 3.

[0130] Compounds of formula 5 are prepared by first preparing a solutionof 2-methyl-2-thiopseudourea (4, 1 equivalent) and alkylchloroformate (2equivalents) in water at 0° C. To this solution is added 25% aqueoussodium hydroxide in a dropwise fashion over 1 hour until the pHstabilized at 8. Acetic acid is then added to achieve pH 5 then sodiumacetate trihydrate (1 eauivalent) and a solution of 3 (1 equivalent) inROH are added. p-Toluenesulfonic acid (catalytic amount) is added andthe resulting mixture heated at reflux for 1 hour. The reaction mixtureis then cooled to ambient temperature and diluted with ethyl acetate.After aqueous work-up, the crude product is purified by preparative HPLCto afford 5.

[0131] Scheme II above shows an alternative method for preparingcompound 2. Starting material 1 (1 equivalent) is combined withbis(pinacolato)diboron (1.2 equivalents), PdCl₂(dppf) (0.1 equivalent),and KOAc (3 equivalents) in DMSO, and the resulting mixture is heated at80° C. for 18 hours. The reaction mixture is cooled to ambienttemperature then the aryl bromide (1.1 equivalents) is added followed bythe further addition of K₃PO₄ (3 equivalents) and PdCl₂(dppf) (0.1equivalent). The resulting mixture is heated at 95° C. for another 72hours then allowed to cool to room temperature. Purification bychromatography affords compound 2.

[0132] Using the preparation of compound number Ia-84 to illustrate,Scheme III above shows the general method used for preparing compoundsof formula IIa. Starting material 6 is prepared according to the methoddescribed in Scheme I at steps (a) and (b). Compound 7 is prepared bytreating 6 with cyanogen bromide in acetonitrile at room temperatureover night. Aqueous work-up affords 7. Compound Ia-84 is prepared from 7by treating with ethyl isocyanate in THF at reflux over night. The crudeproduct is purified by preparative chromatography to afford Ia-84.

[0133] Using the preparation of compound number Ia-86 to illustrate,Scheme IV above shows a general method that may be used for preparingcompounds of formula IIIa. Compound 10 is prepared from5-bromo-2-chloropyrimidine (8) and N-Boc-ethylenediamine (9) by heatinga mixture of 8 and 9 in ethanol at 80° C. for 4 hours. Compound 12 isprepared from 10 and 11 according to the method described in Scheme II.Compound 12 is used to prepare Ia-86 via steps (c) and (d) according tosteps (b) and (c) of Scheme I.

[0134] Using the preparation of compound number Ib-1 to illustrate,Scheme V above shows a general method that may be used for preparingcompounds of formula Ib. Compound 16 is prepared from 15 according tothe method described in Scheme III, step (a). Compound Ib-1 is preparedby treating 16 with ethylchloroformate in pyridine.

[0135] Using the preparation of compound number Ib-3 to illustrate,Scheme VI above shows a general method that may be used for preparingcompounds of formula IIb. Compound 16 is treated ethyl isocyanate in THFat reflux according to Scheme III step, (b) to afford Ib-3.

[0136] Scheme VII above shows a general method for preparing compoundsof this invention wherein R¹ is imidazol-1-yl. In step (a),dinitrofluorobenzene (17) is combined with methyl-4-imidazolecarboxylate(18) in THF and treated with sodium hydride at 0° C. After 3 hours, thereaction mixture is diluted with toluene and acidified with HCl. Thephases are separated and the aqueous phase washed with toluene, cooledto 0° C., and basified with conc. NH₄OH. Ethyl acetate is added and theresulting mixture stirred until all solids dissolved. The phases areseparated and the organic phase washed with brine, dried over Na₂SO₄,then filtered and the filtrate concentrated in vacuo. The mixture ofregioisomers are separated and purified via flash chromatography (silicagel, 5%-->20% ethanol/ethyl acetate gradient) to afford the desiredadduct 19 as an off-white solid.

[0137] Compound 19 is used to prepare compounds Ia-156, Ia-157, andIa-170 in a manner substantially similar to the methods described abovefor Scheme III.

[0138] A preferred embodiment of this invention relates to a method oftreating a bacterial infection in a mammal in need thereof, comprisingthe step of administering to said mammal a therapeutically effectiveamount of a compound having the formula IIa or IIb:

[0139] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0140] W is nitrogen or CR^(a);

[0141] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷ or—N(R⁷)₂;

[0142] R¹ is an aryl or heteroaryl ring, wherein said ring is optionallysubstituted by up to four R⁹; wherein an R⁹ substituent in theortho-position of R¹ taken together with R² may form a fused,unsaturated or partially unsaturated, optionally substituted 5-8membered ring having 0-2 ring heteroatoms selected from nitrogen,oxygen, or sulfur;

[0143] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated-or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0144] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0145] y is 1-6;

[0146] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0147] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0148] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0149] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0150] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂;

[0151] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0152] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; and

[0153] each m and n are independently selected from zero or one.

[0154] Another preferred embodiment of this invention relates to amethod of treating a bacterial infection in a mammal in need thereof,comprising the step of administering to said mammal a therapeuticallyeffective amount of a compound of formula IIIa or IIIb:

[0155] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0156] W is nitrogen or CR^(a);

[0157] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or—N(R⁶)₂;

[0158] Ring A is optionally substituted with up to three R⁹; whereinwhen an R⁹ substituent is in the ortho-position of Ring A, said R⁹substituent may be taken together with R² to form an optionallysubstituted 5-7 membered ring containing 0-2 ring heteroatoms selectedfrom nitrogen, oxygen, or sulfur;

[0159] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0160] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0161] y is 1-6;

[0162] R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R,(CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂,CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂;

[0163] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0164] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0165] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0166] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0167] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO (OR⁷)₂;

[0168] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0169] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—;

[0170] each m and n are independently selected from zero or one;

[0171] and R¹⁰ is selected from R⁷ or Ar.

[0172] According to another embodiment, the invention provides a methodof decreasing bacterial quantity in a biological sample. This methodcomprises the step of contacting said biological sample with a compoundof formula I:

[0173] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0174] Z is O or N—R⁴;

[0175] W is nitrogen or CR^(a);

[0176] R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷ or—N(R⁷)₂;

[0177] R¹ is an aryl or heteroaryl ring, wherein said ring is optionallysubstituted by up to four R⁹; wherein an R⁹ substituent in theortho-position of R¹ taken together with R² may form a fused,unsaturated or partially unsaturated, optionally substituted 5-8membered ring having 0-2 ring heteroatoms selected from nitrogen,oxygen, or sulfur;

[0178] R² and R³ are each independently selected from R⁶, halogen, CN,SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶,CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are takentogether to form a fused, unsaturated or partially unsaturated,optionally substituted 5-8 membered ring containing 0-2 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0179] R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶,SO₂N(R⁶)₂, or (CH₂)_(y)R²;

[0180] y is 1-6;

[0181] R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R,(CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂,CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂,

[0182] Ar is a five membered heteroaryl, heterocyclyl, or carbocyclylring, wherein said ring is optionally substituted by up to threesubstituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸,NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸;

[0183] each R⁶ is independently selected from R⁷ or an optionallysubstituted group selected from alkoxy, hydroxyalkyl, heterocyclyl,heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl,heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;

[0184] each R⁷ is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons, or two R⁷ on thesame nitrogen taken together with the nitrogen optionally form a four tosix member, saturated or unsaturated heterocyclic ring having one tothree heteroatoms;

[0185] R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacentpositions of Ar, or an aryl or heteroaryl ring, may be taken togetherwith their intervening atoms to form a three to six membered fused ring;

[0186] each R⁹ is independently selected from oxo, halogen, CN, NO₂,T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶,CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶,N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶,N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂,N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂,T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂;

[0187] each Q is an independently selected C₁-C₃ branched or straightalkyl;

[0188] T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—;

[0189] each m and n are independently selected from zero or one;

[0190] and R¹⁰ is selected from R⁷ or Ar.

[0191] The term “biological sample”, as used herein, includes cellcultures or extracts thereof; biopsied material obtained from a mammalor extracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof. The term “biological sample” alsoincludes living organisms, in which case “contacting a compound of thisinvention with a biological sample” is synonymous with the term“administrating said compound (or composition comprising said compound)to a mammal.”

[0192] A preferred embodiment comprises contacting said biologicalsample with a compound of formula Ia, Ib, IIa, IIb, IIIa, IIIb, or acompound listed in either of Tables 1 and 2. Pharmaceutical compositionsuseful for such methods are described below.

[0193] The compounds of this invention are potent inhibitors of gyraseas determined by enzymatic assay. These compounds have also been shownto have antimicrobial activity in an antimicrobial susceptibility assay.The details of the conditions used for both the enzymatic and theantimicrobial susceptibility assays are set forth in the Examples below.

[0194] The gyrase inhibitors of this invention, or pharmaceutical saltsthereof, may be formulated into pharmaceutical compositions foradministration to animals or humans. These pharmaceutical compositionseffective to treat or prevent a bacterial infection which comprise thegyrase inhibitor in an amount sufficient to measurably decreasebacterial quantity and a pharmaceutically acceptable carrier, areanother embodiment of the present invention. The term “measurablydecrease bacterial quantity”, as used herein means a measurable changein the number of bacteria between a sample containing said inhibitor anda sample containing only bacteria.

[0195] Agents which increase the susceptibility of bacterial organismsto antibiotics are known. For example, U.S. Pat. Nos. 5,523,288,5,783,561 and 6,140,306 describe methods of usingbactericidal/permeability-increasing protein (BPI) for increasingantibiotic susceptibility of gram-positive and gram-negative bacteria.Agents that increase the permeability of the outer membrane of bacterialorganisms have been described by Vaara, M. in Microbiological Reviews(1992) pp. 395-411, and the sensitization of gram-negative bacteria hasbeen described by Tsubery, H., et al, in J. Med. Chem. (2000) pp.3085-3092.

[0196] Another preferred embodiment of this invention relates to amethod, as described above, of treating a bacterial infection in amammal in need thereof, but further comprising the step of administeringto said mammal an agent which increases the susceptibility of bacterialorganisms to antibiotics.

[0197] According to another preferred embodiment, the invention providesa method, as described above, of decreasing bacterial quantity in abiological sample, but further comprising the step of contacting saidbiological sample with an agent which increases the susceptibility ofbacterial organisms to antibiotics.

[0198] The pharmaceutical compositions and methods of this inventionwill be useful generally for controlling bacterial infections in vivo.Examples of bacterial organisms that may be controlled by thecompositions and methods of this invention include, but are not limitedto the following organisms: Streptococcus pneumoniae, Streptococcuspyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiellapneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E.coli, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph,Haemophilus infuenzae, Bacillus anthracis, Mycoplasma pneumoniae, andStaphylococcus epidermitidis. The compositions and methods willtherefore be useful for controlling treating or reducing theadvancement, severity or effects of nosocomial or non-nosocomialinfections. Examples of nosocomial uses include, but are not limited to,urinary tract infections, pneumonia, surgical wound infections, andbacteremia. Examples of non-nosocomial uses include but are not limitedto urinary tract infections, pneumonia, prostatitis, skin and softtissue infections, intra-abdominal infections, and therapy for febrileneutropenic patients.

[0199] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

[0200] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a mammal (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0201] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

[0202] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2,-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0203] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺ (C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0204] Pharmaceutical compositions of this invention comprise a compoundof formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier. Such compositions may optionallycomprise an additional therapeutic agent. Such agents include, but arenot limited to, an antibiotic, an anti-inflammatory agent, a matrixmetalloprotease inhibitor, a lipoxygenase inhibitor, a cytokineantagonist, an immunosuppressant, an anti-cancer agent, an anti-viralagent, a cytokine, a growth factor, an immunomodulator, a prostaglandinor an anti-vascular hyperproliferation compound.

[0205] The term “pharmaceutically acceptable carrier” refers to anon-toxic carrier that may be administered to a patient, together with acompound of this invention, and which does not destroy thepharmacological activity thereof.

[0206] Pharmaceutically acceptable carriers that may be used in thepharmaceutical compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat and self-emulsifying drug delivery systems (SEDDS) such asα-tocopherol, polyethyleneglycol 1000 succinate, or other similarpolymeric delivery matrices.

[0207] The term “pharmaceutically effective amount” refers to an amounteffective in treating or ameliorating a bacterial infection in apatient. The term “prophylactically effective amount” refers to anamount effective in preventing or substantially lessening a bacterialinfection in a patient.

[0208] Depending upon the particular condition, or disease state, to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. Such therapeutic agentsinclude, but are not limited to, an antibiotic, an anti-inflammatoryagent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, acytokine antagonist, an immunosuppressant, an anti-cancer agent, ananti-viral agent, a cytokine, a growth factor, an immunomodulator, aprostaglandin or an anti-vascular hyperproliferation compound.

[0209] The compounds of this invention may be employed in a conventionalmanner for controlling bacterial infections levels in vivo and fortreating diseases or reducing the advancement or severity of effectswhich are mediated by bacteria. Such methods of treatment, their dosagelevels and requirements may be selected by those of ordinary skill inthe art from available methods and techniques.

[0210] For example, a compound of this invention may be combined with apharmaceutically acceptable adjuvant for administration to a patientsuffering from a bacterial infection or disease in a pharmaceuticallyacceptable manner and in an amount effective to lessen the severity ofthat infection or disease.

[0211] Alternatively, the compounds of this invention may be used incompositions and methods for treating or protecting individuals againstbacterial infections or diseases over extended periods of time. Thecompounds may be employed in such compositions either alone or togetherwith other compounds of this invention in a manner consistent with theconventional utilization of enzyme inhibitors in pharmaceuticalcompositions. For example, a compound of this invention may be combinedwith pharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against bacterialinfections or diseases.

[0212] The compounds of formula I may also be Co-administered with otherantibiotics to increase the effect of therapy or prophylaxis againstvarious bacterial infections. When the compounds of this invention areadministered in combination therapies with other agents, they may beadministered sequentially or concurrently to the patient. Alternatively,pharmaceutical or prophylactic compositions according to this inventioncomprise a combination of a compound of formula I and anothertherapeutic or prophylactic agent.

[0213] The additional therapeutic agents described above may beadministered separately, as part of a multiple dosage regimen, from theinhibitor-containing composition. Alternatively, these agents may bepart of a single dosage form, mixed together with the inhibitor in asingle composition.

[0214] The pharmaceutical compositions of this invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

[0215] The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using.suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent;for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as those described in Pharmacopeia Helvetica, or asimilar alcohol.

[0216] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions and solutions and propylene glycol are administeredorally, the active ingredient is combined with emulsifying andsuspending agents. If desired, certain sweetening and/or flavoringand/or coloring agents may be added.

[0217] The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

[0218] Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-administered transdermalpatches are also included in this invention.

[0219] The pharmaceutical compositions of this invention may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

[0220] Dosage levels of between about 0.01 and about 100 mg/kg bodyweight per day, preferably between 0.5 and about 75 mg/kg body weightper day and most preferably between about 1 and 50 mg/kg body weight perday of the active ingredient compound are useful in a monotherapy forthe prevention and treatment of bacterial infections caused by bacteriasuch as Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcusfecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps.Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, S.aureus, and Coag. Neg. Staph.

[0221] Typically, the pharmaceutical compositions of this invention willbe administered from about 1 to 5 times per day or alternatively, as acontinuous infusion. Or, alternatively, the compositions of the presentinvention may be administered in a pulsatile formulaion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 2.0% to about 80% active compound.

[0222] When the compositions of this invention comprise a combination ofa compound of formula I and one or more additional therapeutic orprophylactic agents, both the compound and the additional agent shouldbe present at dosage levels of between about 10% to 80% of the dosagenormally administered in a monotherapy regime.

[0223] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence or disease symptoms.

[0224] As the skilled artisan will appreciate, lower or higher dosesthan those recited above may be required. Specific dosage and treatmentregimens for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health status, sex, diet, time ofadministration, rate of excretion, drug combination, the severity andcourse of the disease, and the patient's disposition to the disease andthe judgment of the treating physician.

[0225] According to another embodiment, the invention provides methodsfor treating or preventing a bacterial infection, or disease state,comprising the step of administering to a patient any compound,pharmaceutical composition, or combination described herein. The term“patient”, as used herein, means an animal, preferably a mammal, andmost preferably a human.

[0226] The compounds of this invention are also useful as commercialreagents which effectively bind to the gyrase B enzyme. As commercialreagents, the compounds of this invention, and their derivatives, may beused to block gyrase B activity in biochemical or cellular assays forbacterial gyrase B or its homologs or may be derivatized to bind to astable resin as a tethered substrate for affinity chromatographyapplications. These and other uses which characterize commercial gyraseB inhibitors will be evident to those of ordinary skill in the art.

[0227] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES Example 1

[0228]

[0229] 4-(Pyridin-3-yl)-2-nitroaniline (2): To a solution of4-bromo-2-nitroaniline (217 mg, 1 mmol) in DMF (6 mL) was added3-pyridine boronic acid (148 mg, 1.2 mmol), potassium phosphate (276 mg,1.3 mmol), and dichloro-(diphenylphosphinoferrocene)palladium (75 mg,0.1 mmol).

[0230] The resulting mixture was heated at 95° C. for 18 hours thencooled to room temperature and diluted with ethyl acetate (80 mL). Theresulting solution was washed successively with saturated aqueous sodiumbicarbonate, water, and brine, dried over magnesium sulfate thenconcentrated in vacuo. The concentrate was purified by chromatography[Silica Gel, ethyl acetate: hexanes (1:3)→(1:2)] to afford compound 2(117 mg, 54%). ¹H NMR (CDCl₃) δ8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H),7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m, 1H), 6.95 (d, 1H), 6.25 (br s,2H).

Example 2

[0231]

[0232] 4-Pyridin-3-yl-benzene-1,2-diamine (3): To a solution of compound2 (117 mg, 0.54 mmol) in ethyl acetate (13 mL) was added 10% palladiumon carbon (51 mg). The resulting suspension was placed in a Parrhydrogenation apparatus under 40 psi hydrogen gas while shaking atambient temperature for 2 hours. The catalyst was removed by filtrationand the filtrate concentrated in vacuo to afford compound 2 (115 mg,quantitative yield). ¹H NMR (CDCl₃)δ8.8 (m, 1H), 8.45 (m, 1H), 7.75 (m,1H), 7.25 (m, 1H), 6.95 (m, 2H), 6.80 (m, 1H), 3.25 (br s, 4H).

Example 3

[0233]

[0234] (5-Pyridin-3-yl-1H-benzoimidazol-2-yl)-carbamic acid ethyl ester(Ia-11): To a solution of 2-methyl-2-thiopseudourea (151 mg, 0.54 mmol)and ethylchloroformate (0.103 mL, 1.08 mmol) in water (2 mL) at 0° C.was added 25% aqueous sodium hydroxide in a dropwise fashion over 1 houruntil the pH stabilized at 8. Enough acetic acid was then added toachieve pH 5 then sodium acetate trihydrate (74 mg, 0.54 mmol) and asolution of 2 (0.54 mmol) in ethanol (3 mL) were added. A catalyticamount of p-toluenesulfonic acid was added and the resulting mixture washeated at reflux for 1 hour. The reaction mixture was then cooled toambient temperature and diluted with ethyl acetate (50 mL). The organicsolution was washed with aqueous NaOH, water, and brine then dried overmagnesium sulfate and concentrated in vacuo. The crude product waspurified by preparative HPLC to afford compound Ia-11. ¹H NMR (CDCl₃)δ9.1 (s, 1H), 8,75 (d, 1H), 8.5 (d, 1H), 7.9 (s, 1H), 7.8 (m, 1H), 7.65(m, 2H), 4.3 (q, 2H), 1.3 (t, 3H). (M+1)283.

Example 4

[0235]

[0236] 5-Phenyl-1H-benzoimidazol-2-ylamine (7): To a solution ofbiphenyl-3,4-diamine (0.99 mmol) in THF:MeOH:water (5 mL:10 mL:10 mL)was added cyanogen bromide (5M solution in acetonitrile, 1.06 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was partitioned between EtOAc and aqueous sodium hydroxide andthe aqueous layer re-extracted with EtOAc. The combined EtOAc extractswere washed with water, brine, dried over MgSO₂, then concentrated invacuo to afford 7 (147 mg, 71%) as an off-white solid.

Example 5

[0237]

[0238] 1-Ethyl-3-(5-phenyl-1H-benzoimidazol-2-yl)-urea (Ia-84): To asolution of 7 (40 mg, 0.19 mmol) in THF (1 mL) was added ethylisocyanate (27 μL, 0.34 mmol) as a solution in THF (0.5 mL). Thereaction was heated to reflux overnight then concentrated in vacuo. Thecrude product was purified by preparative HPLC to afford Ia-84.

Example 6

[0239]

[0240] [2-(5-Bromo-pyrimidin-2-ylamino)-ethyl]-carbamic acid tert-butylester (10): A mixture of 5-bromo-2-chloropyrimidine (500 mg),N-Boc-ethylenediamine (496 mg), and triethylamine (1 mL) in ethanol (10mL) was heated at 80° C. for 4 hours. The reaction was then concentratedin vacuo and the residue purified by preparative HPLC (hexanes:EtOAc;60:40) to afford compound 10 (700 mg) as a white solid.

Example 7

[0241]

[0242] 1-(3,4-Dinitro-phenyl)-1H-imidazole-4-carboxylic acid methylester (19): To a stirred, 0° C. solution of 1,2-dinitro-4-fluorobenzene(325 mg, 1.74 mmole) and methyl-4-imidazolecarboxylate (200 mg, 1.59mmole) in THF (5 mL) was added NaH (70 mg, 1.74 mmole) in one portion.The resulting mixture was stirred at 0° C. for 3 hours, then dilutedwith toluene and acidified with 6N HCl. The phases were separated andthe aqueous phase washed with toluene, cooled to 0° C., and basifiedwith conc. NH₄OH. Ethyl acetate was added and the resulting mixturestirred until all solids dissolved. Phases separated, organic phasewashed with brine, dried over Na₂SO₄, filtered, concentrated in vacuo.The mixture of regioisomers were separated and purified via flashchromatography (silica gel, 5%-->20% ethanol/ethyl acetate gradient) tofford the desired adduct 19 (225 mg, 48%) as an off-white solid. 1H NMR(500 MHz, dmso d6): 8.41 (1H, d); 8.13 (1H, d); 7.5(1H, broad s); 7.28(1H, s); 7.02 (1H, d); 3.80 (3H, s)

Example 8

[0243]

[0244]1-[2-(3-Ethyl-ureido)-3H-benzoimidazol-5-yl]-1H-imiazole-4-carboxylicacid methyl ester (Ia-156): A mixture of 19 (225 mg, 0.770 mmole) and10% Pd-C (catalytic amount) in MeOH (10 mL) was placed under 45 psi ofH₂ (Parr Shaker) overnight. The mixture was filtered, concentrated invacuo, re-diluted with MeCN and MeOH (5 mL/5 mL), and treated withcyanogen bromide (168 mg, 1.54 mmole) at room temperature. The resultingmixture was stirred for 4 hours (precipitate formed), then quenched bythe addition of 7N NH₃—MeOH. The crude reaction was concentrated invacuo and directly flash chromatographed (silica gel, 10%-->35% 7NNH₃—MeOH/CH₂Cl₂ gradient) to give the pure aminobenzimidazole as a whitesolid.

[0245] The purified aminobenzimidazole was diluted in DMSO (1 mL),treated with excess ethyl isocyanate (0.5 mL) and heated to 80° C. for 3hours. The reaction was cooled to room temperature, excess ethylisocyanate removed in vacuo, azeotroped with MeOH (thrice), diluted withMeOH (5 mL), treated with NH4OH (2 mL), and heated to 80° C. for 3hours. The mixture was cooled to room temperature, concentrated invacuo, diluted with 1/1 water/brine, and extracted twice with 4/1 ethylacetate/ethanol. The combined organic extracts were dried over Na₂SO₄,filtered, concentrated in vacuo, and flash chromatographed (silica gel,5%-->30% 2N NH₃—EtOH/CH₂Cl₂ gradient) to give the desired product Ia-156contaminated with ethyl urea. The solid was triturated with water andfiltered to give pure Ia-156 (115 mg, 41% over four steps) as a whitesolid. 1H NMR (500 MHz, dmso-d₆): 11.81 (1H, br s); 9.94 (1H, br d);8.32 (1H, br d); 8.26 (1H, br d); 7.58 (1H, br d); 7.48 (1H, m); 7.28(1H, d); 7.12 (1H, br d); 3.78 (3H, s); 3.20 (2H, dq); 1.12 (3H, t).

Example 9

[0246]

[0247]1-[2-(3-Ethyl-ureido)-3H-benzoimidazol-5-yl]-1H-imidazole-4-carboxylicacid1-[2-(Ethyl-ureido)-3H-benzoimidazol-5-yl]-1H-imidazole-4-carboxylicacid (Ia-157): A solution of Ia-156 (95 mg, 0.289 mmole) in 6N HCl (2mL) was refluxed for 6 hours. The solution was then cooled to roomtemperature, concentrated in vacuo, and azeotroped sequentially withMeOH (twice) and acetone (twice). The resulting solids were suspended inacetone, filtered, and washed with acetone followed by hexanes to giveIa-157 (115 mg, 100%) as a white solid. 1H NMR (500 MHz, dmso-d6): 8.77(1H, m); 8.52 (1H, m); 7.79 (1H, s); 7.72 (1H, m); 7.65 (2H, m); 5.6-4.0(2H, br s); 3.20 (2H, dt); 1.11 (3H, t).

Example 10

[0248]

[0249] A solution of Ia-157 (20 mg, 0.051 mmole) and morpholine (0.050mL, excess) in DMF (1 mL) was treated with PyBrop (20 mg, excess) atroom temperature. The resulting mixture was stirred overnight, thendiluted with 4:1 ethyl acetate:ethanol, washed with 1:1 brine:water(five times), dried over Na₂SO₄. filtered, and flash chromatographed(silica gel, 5%-->20% 2N NH₃—EtOH/CH₂Cl₂ gradient) to give Ia-170 (13mg, 72%) as a white solid. LRMS: 384.5 (M+H)

Example 11

[0250] We have prepared other compounds of formula I by methodssubstantially similar to those described in the above Examples 1-6 andthose illustrated in Schemes I-VI. The characterization data for thesecompounds is summarized in Table 3 below and includes mass spectral (asM+1) and ¹H NMR data.

[0251]¹H NMR data is summarized in Table 3 below wherein “Y” designates¹H NMR data is available and was found to be consistant with structure.Compound numbers correspond to the compound numbers listed in Table 1.TABLE 3 Characterization Data for Selected Compounds No. Ia- M + 1 ¹HNMR No. Ia- M + 1 ¹H NMR 1 282 Y 2 288 Y 3 283 Y 4 283 Y 6 210 Y 7 268 Y8 292 — 9 350 Y 10 296 Y 11 283 Y 12 325 Y 13 324 Y 14 336 Y 15 326 Y 16344 Y 17 361 Y 18 313 Y 19 360 Y 20 399 Y 21 284 Y 22 314 Y 23 312 Y 24326 Y 26 342 Y 33 249 Y 34 298 Y 35 356 Y 36 283 Y 37 428 Y 38 294 Y 39272 Y 40 498 Y 41 452 Y 42 312 Y 43 295.1 Y 44 338 — 45 386 Y 46 320 Y47 382 — 48 389 — 49 418 — 50 311 Y 51 299 Y 52 343 Y 53 368 Y 54 298 Y55 395 Y 56 406 — 57 366 Y 58 296 Y 59 354 Y 60 326 Y 61 440 Y 62 300 Y63 403 — 64 381 — 65 352 — 66 326 — 67 409 Y 69 468 Y 70 368 Y 71 299 Y72 299 Y 73 267 — 74 253 — 75 297 — 76 413 Y 77 371 — 78 282 Y 79 296 Y80 357 Y 81 340 Y 82 280 Y 84 281 Y 85 321 — 86 442 Y 87 370 Y 88 342 —89 359 Y 90 298 Y 91 446 Y 92 329 — 93 499 Y 94 387 Y 97 294 Y 98 389 —100 370 — 101 280 — 102 370 — 103 312 Y 106 409 — 108 300 Y 109 394 —110 467 Y 111 367 Y 112 343 Y 113 409 — 115 298 Y 116 343 — 117 369 —118 282 Y 119 296 Y 120 296 Y 121 322 Y 122 340 Y 124 445 — 125 382 —126 328 Y 127 394 — 128 432 — 129 368 — 130 396 Y 131 316 Y 132 312 Y133 296 Y 134 316 Y 135 410 Y 136 300 Y 137 310 Y 138 388 — 139 352 Y140 401 Y 141 384 Y 142 310 Y 143 511 Y 144 311 Y 145 353 — 146 400 Y147 326 Y 148 411 Y 149 370 Y 150 — — 151 — — 152 317 Y 153 362 Y 154389 Y 155 299 — 156 — — 157 — — 158 — — 159 328 — 160 — — 161 — — 162 —— 163 326 Y 164 367 Y 165 297 Y 166 367 Y 167 350 — 168 298 Y 169 — Y170 — — 171 — — 172 — — 173 — — 174 — — 175 365 Y 176 — Y 177 377 — 178— Y 179 367 Y 180 — Y 181 315 Y 182 366 Y 183 330 Y 184 — — 185 — — 186— — 187 — — 188 — —

Example 12

[0252] Gyrase ATPase Assay

[0253] The ATP hydrolysis activity of DNA gyrase was measured bycoupling the production of ADP through pyruvate kinase/lactatedehydrogenase to the oxidation of NADH. This method has been describedpreviously (Tamura and Gellert, 1990, J. Biol. Chem., 265, 21342).

[0254] ATPase assays are carried out at 30° C. in buffered solutionscontaining 100 mM TRIS pH 7.6, 1.5 mM MgCl₂, 150 mM KCl. The couplingsystem contains (final concentrations)_(2.5) mM phosphoenol pyruvate,200 μM nicotinamide adenine dinucleotide (NADH), 1 mM DTT, 30 ug/mlpyruvate kinase, and 10 ug/ml lactate dehydrogenase. 40 nanomolar enzyme(374 kDa Gyr A2B2 subunit from Staphylococcus aureus) and a DMSOsolution of the inhibitor to a final concentration of 4% are added andthe reaction mixture is allowed to incubate for 10 minutes at 30° C. Thereaction is then started by the addition of ATP to a final concentrationof 0.9 mM and the rate of NADH disappearance at 340 nanometers ismeasured over the course of 10 minutes. The percent inhibition valuesare determined from rate versus concentration profiles and are reportedas the average of duplicate values.

[0255] Table 4 shows the results of the percent inhibition-activity ofselected compounds of this invention in the Gyrase inhibition assay at10 μM concentration. The compound numbers correspond to the compoundnumbers in Table 1. Compounds having an activity designated as “A”provided a percent inhibition value below 50 percent; compounds havingan activity designated as “B” provided a percent inhibition valuebetween 50 and 75 percent; and compounds having an activity designatedas “C” provided a percent inhibition value greater than 75 percent.TABLE 4 Gyrase Inhibitory Activity of Selected Compounds No. Ia-Activity No. Ia- Activity 1 B 2 B 3 B 4 C 6 A 7 A 8 A 9 A 10 A 11 C 12 B13 A 14 B 15 B 16 C 17 C 18 C 19 C 20 A 21 C 22 C 23 C 24 C 26 B 33 A 34C 35 C 36 A 37 C 38 B 39 C 40 C 41 A 42 C 43 C 44 C 45 C 46 A 47 C 48 C49 C 50 B 52 C 53 C 54 C 55 C 56 C 57 C 58 C 59 C 60 C 61 C 62 C 63 C 64C 65 C 66 C 67 C 69 B 70 C 71 A 72 C 73 A 74 A 75 A 76 C 77 C 78 A 79 A80 C 81 B 82 A 84 C 85 A 86 C 87 C 88 C 89 C 90 C 91 A 92 C 93 C 94 C 97A 98 C 100 C 101 A 102 C 103 C 106 C 108 C 109 C 110 C 111 C 112 C 113 C115 A 116 B 117 A 118 C 119 C 120 B 121 A 122 C 124 B 125 C 126 C 127 C128 C 129 C 130 C 131 C 132 C 133 C 134 C 135 C 136 C 137 C 138 C 139 C140 C 141 C 142 C 143 C 144 C 145 C 146 C 147 B 148 C 149 C 150 B 151 C152 C 153 B 154 C 155 A 156 C 157 C 158 C 159 A 160 C 161 A 162 C 163 C164 C 165 C 166 C 167 C 168 C 169 C 170 C 171 C 172 C 173 C 174 C 175 C176 A 177 C 178 C 179 C 180 C 181 B 182 C 183 B 184 B 185 C 186 C 187 C188 C — —

Example 13

[0256] Susceptibility Testing in Liquid Media

[0257] Compounds of this invention were also tested for antimicrobialactivity by susceptibility testing in liquid media. Such assays wereperformed within the guidelines of the latest NCCLS document governingsuch practices: “M7-A5 Methods for dilution Antimicrobial SusceptibilityTests for Bacteria that Grow Aerobically; Approved Standard—FifthEdition (2000)”. Other publications such as “Antibiotics in LaboratoryMedicine” (Edited by V. Lorian, Publishers Williams and Wilkins, 1996)provide essential practical techniques in laboratory antibiotic testing.Essentially, several discrete bacterial colonies (3 to 7) from a freshlystreaked plate were transferred to an appropriate rich broth medium suchas MHB, supplemented where appropriate for the more fastidiousorganisms. This was grown overnight to high density followed by a 1 or2-thousand-fold dilution to give an inoculation density of between 5×10⁵and 5×10⁶ CFU per mL. Alternatively, the freshly picked colonies can beincubated at 37° C. for about 4 to 8 hrs until the culture equals orexceeds a turbidity of a 0.5 McFarland standard (approximately 1.5×10⁸cells per mL) and diluted to give the same CFU per mL as above. In amore convenient method, the inoculum was prepared using a commerciallyavailable mechanical device (the BBL PROMPT System) that involvestouching five colonies directly with a wand, containing crosshatchgrooves at its bottom, followed by suspension of the bacteria in anappropriate volume of saline. Dilution to the appropriate inoculum celldensity was made from this cell suspension. The broth used for testingconsists of MHB supplemented with 50 mg per L of Ca²⁺ and 25 mg per L ofMg²⁺. Standard dilution panels of control antibiotics were made andstored as in the NCCLS standard M7-A5, the dilution range typicallybeing in the 128 μg per mL to 0.015 μg per mL (by 2-fold serialdilution). The test compounds were dissolved and diluted fresh forexperimentation on the same day; the same or similar ranges ofconcentration as above being used. The test compounds and controls weredispensed into a multiwell plate and test bacteria added such that thefinal inoculation was approximately 5×10⁴ CFU per well and the finalvolume was 100 μL. The plates were incubated at 35° C. overnight (16 to20 hr) and checked by eye for turbidity or quantitated with a multiwellplate reader. The endpoint minimal inhibitory concentration (MIC) is thelowest concentration of drug at which the microorganism tested does notgrow. Such determinations were also compared to the appropriate tablescontained in the above two publications to ensure that the range ofantibacterial activity is within the acceptable range for thisstandardized assay.

[0258] Table 5 shows the results of the MIC assay for selected compoundsof this invention. The compound numbers correspond to the compoundnumbers in Table 1. Compounds having an activity level designated as “A”provided an MIC of less than 10 μg/mL; compounds having an activitylevel designated as “B” provided an MIC of between 10 and 40 μg/mL;compounds having an activity level designated as “C” provided an MIC ofgreater than 40 μg/mL. TABLE 5 MIC Values of Selected Compounds No. Ia-Activity No. Ia- Activity 42 B 58 A 90 A 92 A 98 B 112 A 116 C 117 C 118A 119 C 120 C 121 C 122 C 133 A 137 C 138 C 139 C 140 A 141 A 142 A 144B 145 B 146 A 147 C 148 B 149 C 150 C 151 C 152 B 153 C 154 C 156 B 157C 158 C 159 C 160 C 161 C 162 C 163 A 164 C 165 B 166 C 167 C 168 A 169B 170 C 171 B 173 B 174 C 175 C 177 C 178 A 179 C 180 B 181 C 182 C 183C 184 C 185 C 186 A 187 B 188 A 196 B 197 B 198 B — —

[0259] While we have described a number of embodiments of thisinvention, it is apparent that our basic constructions may be altered toprovide other embodiments which utilize the products and processes ofthis invention.

We claim:
 1. A method of decreasing bacterial quantity in a biological sample comprising the step of contacting said biological sample with a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z is O or N—R⁴; W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; R¹ is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R⁹; wherein an R⁹ substituent in the ortho-position of R¹ taken together with R² may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R, (CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂, CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; each m and n are independently selected from zero or one; and R¹⁰ is selected from R⁷ or Ar.
 2. The method according to claim 1, wherein said compound has the formula Ia or Ib:

or a pharmaceutically acceptable derivative or prodrug thereof.
 3. The method according to claim 2, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (c) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (d) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 4. The method according to claim 3, wherein: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (c) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (d) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 5. The method according to claim 3, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; (e) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (f) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 6. The method according to claim 5, wherein: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; (e) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (f) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 7. The method according to claim 1, wherein said compound has the formula IIa or IIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; R¹ is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R⁹; wherein an R⁹ substituent in the ortho-position of R¹ taken together with R² may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; and each m and n are independently selected from zero or one.
 8. The method according to claim 7, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 9. The method according to claim 8, wherein: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 10. The method according to claim 8, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 11. The method according to claim 10, wherein: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 12. The method according to claim 1, wherein said compound has the formula IIIa or IIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; Ring A is optionally substituted with up to three R⁹; wherein when an R⁹ substituent is in the ortho-position of Ring A, said R⁹ substituent may be taken together with R² to form an optionally substituted 5-7 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R, (CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂, CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸, or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; each m and n are independently selected from zero or one; and R¹⁰ is selected from R⁷ or Ar.
 13. The method according to claim 12, wherein said compound has one or more features selected from the group consisting of: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 14. The method according to claim 13, wherein: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 15. The method according to claim 13, wherein said compound has one or more features selected from the group consisting of: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 16. The method according to claim 15, wherein: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 17. The method according to claim 1, wherein said compound is selected from those listed in either of Tables 1 or
 2. 18. The method according to claim 1 further comprising the step of contacting said biological sample with an agent which increases the susceptibility of bacterial organisms to antibiotics.
 19. A method of treating a bacterial infection in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z is O or N—R⁴; W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; R¹ is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R⁹; wherein an R⁹ substituent in the ortho-position of R¹ taken together with R² may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R, (CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂, CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; each m and n are independently selected from zero or one; and R¹⁰ is selected from R⁷ or Ar.
 20. The method according to claim 19, wherein said compound has the formula Ia or Ib:

or a pharmaceutically acceptable derivative or prodrug thereof.
 21. The method according to claim 20, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (c) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (d) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 22. The method according to claim 21, wherein: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (c) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (d) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 23. The method according to claim 21, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; (e) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (f) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 24. The method according to claim 23, wherein: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; (e) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (f) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 25. The method according to claim 19, wherein said compound has the formula IIa or IIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; R¹ is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R⁹; wherein an R⁹ substituent in the ortho-position of R¹ taken together with R² may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; and each m and n are independently selected from zero or one.
 26. The method according to claim 25, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 27. The method according to claim 26, wherein: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 28. The method according to claim 26, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 29. The method according to claim 28, wherein: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 30. The method according to claim 19, wherein said compound has the formula IIIa or IIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; Ring A is optionally substituted with up to three R⁹; wherein when an R⁹ substituent is in the ortho-position of Ring A, said R⁹ substituent may be taken together with R² to form an optionally substituted 5-7 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R, (CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂, CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸; COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; each m and n are independently selected from zero or one; and R¹⁰ is selected from R⁷ or Ar.
 31. The method according to claim 30, wherein said compound has one or more features selected from the group consisting of: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 32. The method according to claim 31, wherein: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, Oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 33. The method according to claim 31, wherein said compound has one or more features selected from the group consisting of: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 34. The method according to claim 33, wherein: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 35. The method according to claim 19, wherein said compound is selected from those listed in either of Tables 1 and
 2. 36. The method according to claim 19, wherein the disease in mammals is alleviated by administration of an inhibitor of gyrase.
 37. The method according to claim 19, wherein the bacterial infection to be treated is characterized by the presence of one or more of the following: Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, S. aureus, or Coag. Neg. Staph.
 38. The method according to claim 19, wherein the bacterial infection to be treated is selected from one or more of the following: urinary tract infections, pneumonia, prostatitis, skin and soft tissue infections, intra-abdominal infections, or infections of febrile neutropenic patients.
 39. The method according to claim 19 further comprising the step of administering to said patient an additional therapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.
 40. The method according to claim 19 further comprising the step of administering to said patient an agent that increases the susceptibility of bacterial organisms to antibiotics.
 41. A compound of formula IIa or IIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷, or —N(R⁷)₂; R¹ is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R⁹; wherein an R⁹ substituent in the ortho-position of R¹ taken together with R² may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; and each m and n are independently selected from zero or one.
 42. The compound according to claim 41, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 43. The compound according to claim 42, wherein: (a) R¹ is an optionally substituted aryl or heteroaryl ring; (b) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 44. The compound according to claim 42, wherein said compound has one or more features selected from the group consisting of: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 45. The compound according to claim 44, wherein: (a) R¹ is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (d) R⁴ is hydrogen or (CH₂)_(y)R²; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 46. A compound of formula IIIa or IIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: W is nitrogen or CR^(a); R^(a) is selected from hydrogen, halogen, —CF₃, R⁷, —OR⁷ or —N(R⁷)₂; Ring A is optionally substituted with up to three R⁹; wherein when an R⁹ substituent is in the ortho-position of Ring A, said R⁹ substituent may be taken together with R² to form an optionally substituted 5-7 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R² and R³ are each independently selected from R⁶, halogen, CN, SR⁶, OR⁶, N(R⁶)₂, NRCO₂R⁶, NRCON(R⁶)₂, CON(R⁶)₂, NRCOR⁶, NRN(R⁶)₂, COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or NRSO₂R⁶; or R² and R³ are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R⁴ is selected from R⁶, CON(R⁶), COR⁶, CO₂R⁶, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, or (CH₂)_(y)R²; y is 1-6; R⁵ is selected from R⁷, Ar, COAr, CON(R⁷)Ar, (CH₂)_(y)CO₂R, (CH₂)_(y)N(R⁷)₂, C(═NR¹⁰)—N(R⁷)₂, C(═NR¹⁰)—NRCOR, C(═S)—N(R⁷)₂, CON(R⁷)₂, COR, SO₂R, or SO₂N(R⁷)₂; Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO₂, R⁸, OR⁸, NHR⁸, NHCOR⁸, NHCONHR⁸, COR⁸, CONHR⁸, SO₂R⁸, NHSO₂NHR⁸ or SO₂NHR⁸; each R⁶ is independently selected from R⁷ or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl; each R⁷ is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R⁷ on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms; R⁸ is a C₁-C₄ aliphatic group, wherein two R⁸ on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring; each R⁹ is independently selected from oxo, halogen, CN, NO₂, T_(n)(haloalkyl), R⁶, SR⁶, OR⁶, OR⁸, N(R⁶)₂, CON(R⁶)₂, CON(R)COR⁶, COR⁶, CO₂R⁶, CO₂N(R⁶)₂, COCOR⁶, SO₂R⁶, SO₂N(R⁶)₂, N(R)T_(n)CO₂R⁶, N(R)T_(n)CON(R⁶)₂, N(R)T_(n)N(R⁶)₂, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)NRCON(R⁶)₂, N(R)T_(n)COR⁶, N(R)T_(n)NRCOR⁶, N(R)T_(n)SO₂N(R⁶)₂, N(R)T_(n)SO₂R⁶, T_(n)PO(OR⁷)₂, T_(n)OPO(OR⁷)₂, T_(n)SP(OR⁷)₂, T_(n)PO(OR⁷)₂, or T_(n)NPO(OR⁷)₂; each Q is an independently selected C₁-C₃ branched or straight alkyl; T is selected from —Q— or —Q_(m)—CH(Q_(m)—R²)—; each m and n are independently selected from zero or one; and R¹⁰ is selected from R⁷ or Ar.
 47. The compound according to claim 46, wherein said compound has one or more features selected from the group consisting of: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 48. The compound according to claim 47, wherein: (a) R² and R³ are each independently selected from halogen, CN, CO₂R⁶, OR⁶, or R⁶; (b) R⁵ is CO₂R, COAr, COR, CON(R⁷)₂, Ar, (CH₂)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (c) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, N(R)T_(n)CO₂R⁶, N(R)T_(n)NRCO₂R⁶, N(R)T_(n)N(R⁶)₂, NO₂, T_(n)(haloalkyl), CO₂N(R⁶)₂, COR⁶, SO₂R⁶, or SO₂N(R⁶)₂.
 49. The compound according to claim 47, wherein said compound has one or more features selected from the group consisting of: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R)COR⁶, or N(R)T_(n)CO₂R⁶.
 50. The compound according to claim 49, wherein: (a) R² is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R³ is hydrogen, alkoxy, aralkoxy, or halogen; (c) R⁴ is hydrogen or (CH₂)_(y)R²; (d) R⁵ is CON(R⁷)₂, Ar, (CH₂)_(y)CO₂R, or (CH₂)_(y)N(R⁷)₂; and (e) R⁹ is halogen, CN, oxo, R⁶, SR⁶, OR⁶, N(R⁶)₂, CON(R⁶)₂, CO₂R⁶, CON(R⁶)COR⁶, or N(R)T_(n)CO₂R⁶.
 51. A composition comprising a compound according to any one of claims 41 to 50; and a pharmaceutically acceptable carrier.
 52. The composition according to claim 51, wherein said compound is formulated in a pharmaceutically acceptable manner for administration to a patient.
 53. The composition according to claim 51 further comprising an additional therapeutic agent.
 54. The composition according to claim 52 further comprising an additional therapeutic agent.
 55. The composition according to claim 51 further comprising an agent that increases the susceptibility of bacterial organisms to antibiotics.
 56. The composition according to claim 53 further comprising an agent that increases the susceptibility of bacterial organisms to antibiotics. 